Sotagliflozin (Zynquista) to be reviewed by the FDA as possible oral adjunct for people with insulin-treated type 1 diabetes.
As of May 22, 2018, a new antidiabetic medication is set to be reviewed by the U.S. Food and Drug Administration. Sotagliflozin (Brand Name: Zynquista), previously referred to as LX4211, is manufactured by two pharmaceutical companies, Sanofi and Lexicon. Sotagliflozin, belonging to the sodium-glucose cotransporter (SGLT) drug class, is quite unique as it acts on not only SGLT2 but SGLT1.
To understand this therapy’s dual-action, a brief discussion of sodium-glucose cotransport isoforms is warranted. The first isoform, SGLT1, located in the small intestine and proximal tubule segment 3, is responsible for the absorption of nutrients and glucose/galactose absorption, respectively. SGLT1 is responsible for only 3% of reabsorption by the kidneys. Conversely, SGLT2, found in the proximal tubule segment 1 and 2, reabsorbs approximately 90% of glucose. One might ask what benefit does dual-inhibition serve. According to Lexicon, they found that mice with reductions in SGLT1, SGLT2, or both isoforms, showed improved glycemic control and metabolism compared to more selective agents.
Now, where exactly does sotagliflozin fit in the pharmacotherapeutic management of a person who has type 1 diabetes? The investigational drug would be used in combination with insulin. Use of this drug as an adjunct would help those patients struggling to achieve glycemic targets.
Sotagliflozin is looking to be approved for the treatment of both type 1 and type 2 diabetes mellitus. Quick review of the medication’s progress through the drug pipeline shows it is progressing more quickly for use in type 1 diabetes, as the FDA has accepted regulatory filing for the drug, while it is presently only in Phase 3 for type 2 diabetes.
Recent progress of the medication in the approval process comes as a result of the inTandem phase 3, double-blind trial. The trial enrolled 1,402 insulin-treated patients with type 1 diabetes. Patients received both insulin and 400mg of sotagliflozin per day (or placebo) for 24 weeks. The primary objective of the study was HbA1c < 7.0% by the end of the study without hypoglycemic events or diabetic ketoacidosis. Secondary endpoints were also determined (i.e. change in HbA1c from baseline, weight, average insulin dose per day, and systolic blood pressure). The results of the study were quite promising, showing that those in the sotagliflozin group achieved the glycemic target more than those receiving placebo (28.6% vs 15.2%; p < 0.001). Additionally, change in HbA1c from baseline (-0.46% points), weight (-2.98kg), systolic blood pressure (-3.5 mmHg) and daily bolus insulin dose per day (-2.8 Units/day) was greater in the treatment group compared to placebo (p ≤ 0.002). Furthermore, instances of severe hypoglycemia were similar in both groups, while other hypoglycemic events (≤ 55 mg/dL) occurred less in the sotagliflozin group. Finally, diabetic ketoacidosis occurred more in the treatment group than in the placebo group (3.0% vs 0.6%).
Currently, SGLT2 inhibitors are indicated for people with type 2 diabetes mellitus as an adjunct for diet and exercise, but not for people with type 1 diabetes. Often, use of oral antidiabetic medications is quite uncommon in people with type 1 diabetes. Still, oral add-ons, like metformin or SGLT2 inhibitors, are used in some cases as some evidence has shown glycemic benefits. However, at this time no oral antidiabetic medications, particularly of the SGLT variety, have been approved for use in people with type 1 diabetes, making Sotagliflozin quite novel.
Overall, Lexicon appears positive about the benefits sotagliflozin can provide to the type 1 diabetes community. Momentum for Zynquista has been gaining this year. On March 29, 2018, Sanofi submitted the application for review to the European Medicines Agency. Executive Vice President and Chief Medical Officer, Pablo Lapuerta, M.D., stated “the acceptance of the NDA filing moves us closer to providing a meaningful option for people with type 1 diabetes.” The target action date for this drug is expected around March 22, 2019.
- As of May 22, 2018, a new dual-acting SGLT inhibitor, Zynquista (sotagliflozin) is set to be reviewed by the U.S. Food and Drug Administration.
- Zynquista, if approved, will be the first oral antidiabetes medication used in combination with insulin in patients diagnosed with type 1 diabetes.
- The inTandem clinical trial found that type 1 diabetes patients taking both insulin and sotagliflozin achieved their glycemic targets (i.e. HbA1c < 7.0%) better than those taking insulin alone; secondary results show that combination therapy reduced mean bolus insulin dose per day, weight, and systolic blood pressure.
- During the inTandem trial, Zynquista users experienced less hypoglycemia, but experienced higher rates of diabetic ketoacidosis.
Woodfield, J. Oral type 1 diabetes medication under FDA review in US. Diabetes Co UK. 24 May 2018. Available from: https://www.diabetes.co.uk/news/2018/may/oral-type-1-diabetes-medication-under-fda-review-in-us-92636261.html.
Poulsen, S., Fenton, R., and Rieg, T. Sodium-glucose cotransport. Curr Opin Nephrol Hypertens. 24.5 (2015): 463-469. doi:10.1097/MNH.0000000000000152.
Garg, S., Henry, R., Banks, P., Buse, J., Davies, M., Gulcher, G., Pozzilli, P., Gesty-Palmer, D., Lapuerta, P., Simo, R., Danne, T., McGuire, D., Kushner, J., Peters, A., Strumph, P. Effects of Sotagliflozin Added to Insulin in Patients with Type 1 Diabetes. N Engl J Med. 377 (2017): 2337-2348. DOI: 10.1056/NEJMoa1708337.
FDA to review Zynquista (sotagliflozin) as potential treatment for type 1 diabetes. Sanofi. 22 May 2018. Available from: http://www.news.sanofi.us/2018-05-22-FDA-to-review-Zynquista-TM-sotagliflozin-as-potential-treatment-for-type-1-diabetes.
EMA to review sotagliflozin as potential treatment for type 1 diabetes. Sanofi. 29 March 2018. Available from: http://mediaroom.sanofi.com/ema-to-review-sotagliflozin-as-potentialtreatment-for-type-1-diabetes-treatment-%E2%80%8B/.
Pipeline: Sotagliflozin (LX4211). Lexicon Pharmaceuticals. Accessed 31 May 2018. Available from: http://www.lexpharma.com/pipeline.
Kaytie A. Weierstahl, Pharm.D. Candidate, LECOM School of Pharmacy